Hypoxia causes neuronal loss, including irreversible damage to the hippocampus, and permanent memory deficiencies. However, it has been shown that short-term treatment with a cholinesterase inhibitor before or immediately after hypoxia prevents at least some of the neuronal loss and this treatment can change the long-term outcome, preserving both the the neuronal tissue and cognitive function. The objective of this research program is to understand the contributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in protecting against hypoxia-induced neuronal losses and amnesia. A weakness in the previous research is that the specific role of AChE or BChE was not determined. The specific aim of the research is to determine if protection against hypoxia is most effectively mediated by AChE or BChE inhibition, or both. Experiment One will establish a reliable model of carbon monoxide (CO) and sodium nitrite (SN) induced hypoxia in rats. Reductions of cytochrome oxidase activity in the hippocampus and cortex will be used to measured hypoxia-induced neuronal loss and the correlated amnesia will be measured by a radial arm maze task. Experiment Two will determine to what extent hypoxia-induced changes can be prevented with treatment of selective inhibitors of AChE or BChE before hypoxia. Experiment three will determine whether or not treatment with selective inhibitors of AChE or BChE given after hypoxia can reduce or prevent hypoxia-induced damage. The results of these experiments will assist in the rational development of new strategies for treating brain hypoxia and ischemia.